Evaluation of mpox contact tracing activities and data collection in EU/EEA countries during the 2022 multicountry outbreak in nonendemic countries.

To control human-to-human mpox transmission during the 2022 outbreak, European Union (EU)/European Economic Area (EEA) countries conducted case investigation and contact tracing (CT). We aimed to provide an overview of CT activities, describe CT data collection practices, and identify related facilitators, barriers, and potential opportunities for improvement. Between April 03, 2023 and May 12, 2023, a survey was distributed to CT stakeholders in 30 EU/EEA countries, asking about mpox CT activities and data collection and requesting to rank enablers, barriers, and improvements for CT on a five-point Likert scale. The 139 respondents from 27 countries indicated having performed case investigations (96%, n = 133), backward CT (88%, n = 122), forward CT (87%, n = 121), and follow-up on contacts' outcomes (77%, n = 107). Sixty percent (n = 80/134) used standardized data collection forms and 73% (n = 91/124) used databases. The highest-rated enablers were clear guidelines (mean = 3.9), quick access to laboratory results (3.6), and sufficient expertise (3.6). Highly rated barriers were inability to contact contacts (3.0) or cases (2.5) and lack of staff (2.4). The most needed improvements were availability of staff (3.5), expertise on affected populations (3.4) and data reporting tools and systems (3.3). To improve CT of mpox and diseases with similar transmission patterns, EU/EEA countries should increase workforce capacity in public and sexual health, offer training on CT operations and communication with affected communities, and use common CT data collection tools and systems.

Statutory health insurance-covered pre-exposure prophylaxis in Germany: changing trends in nationwide tenofovir disoproxil/emtricitabine prescriptions during the COVID-19 pandemic.

Background: In 2019, Germany introduced a law to reimburse high-incidence populations for pre-exposure prophylaxis (PrEP), prescribed as tenofovir-disoproxil/emtricitabine (TDF/FTC), via statutory health insurance (SHI). We studied changes in TDF/FTC-prescriptions after the implementation of this law and during the COVID-19 pandemic. Methods: We performed an interrupted time series analysis with monthly prescriptions per defined time period as the outcome. We considered the introduction of SHI-covered PrEP (09/2019) as an interruption, and four COVID-19 waves and two national lockdowns (2020-2021) as explanatory variables. We extrapolated prescriptions had the lockdowns not occurred, and compared this to the actual prescriptions. We performed sub-analyses based on stratification by five federal states with the highest proportion of PrEP users. We assessed the models' goodness-of-fit based on the adjusted R-squared using RStudio. Results: The best fitting model included SHI-covered PrEP and the first COVID-19 lockdown (04/2020). The decrease in prescriptions during the first lockdown was significant nationally, and in the five federal states for single-month prescriptions. The first lockdown resulted in reductions of 57.7% (95% prediction interval (PI): 23.0%-92.4%) for single-month prescriptions, while 17.4% (95% PI: 0.28%-34.5%) nationally, and 13.9% (95% PI: -3.67%-31.5%) for 3-month prescriptions. Conclusion: Introduction of SHI-covered PrEP resulted in a doubling of TDF/FTC-prescriptions nationwide in the first month alone. A drop in prescriptions was most apparent after the first lockdown, and particularly affected PrEP initiations, possibly due to reduced healthcare access and behavioural changes. Ongoing monitoring of TDF/FTC-prescriptions is needed to safeguard access to preventative care such as PrEP and particularly PrEP initiation during public health crises like COVID-19.

The BAF complex inhibitor pyrimethamine reverses HIV-1 latency in people with HIV-1 on antiretroviral therapy.

Reactivation of the latent HIV-1 reservoir is a first step toward triggering reservoir decay. Here, we investigated the impact of the BAF complex inhibitor pyrimethamine on the reservoir of people living with HIV-1 (PLWH). Twenty-eight PLWH on suppressive antiretroviral therapy were randomized (1:1:1:1 ratio) to receive pyrimethamine, valproic acid, both, or no intervention for 14 days. The primary end point was change in cell-associated unspliced (CA US) HIV-1 RNA at days 0 and 14. We observed a rapid, modest, and significant increase in (CA US) HIV-1 RNA in response to pyrimethamine exposure, which persisted throughout treatment and follow-up. Valproic acid treatment alone did not increase (CA US) HIV-1 RNA or augment the effect of pyrimethamine. Pyrimethamine treatment did not result in a reduction in the size of the inducible reservoir. These data demonstrate that the licensed drug pyrimethamine can be repurposed as a BAF complex inhibitor to reverse HIV-1 latency in vivo in PLWH, substantiating its potential advancement in clinical studies.

HIV transmission among acutely infected participants of a Dutch cohort study 2015-2021 is not associated with large, clustered outbreaks.

OBJECTIVE: Timely identification of acute or early HIV infection (AEHI) is important to help prevent onward transmission, and understanding the number of secondary infections resulting from individuals with AEHI is key to planning HIV prevention services and case finding. DESIGN: We performed a phylogenetic investigation of a dense sample of individuals with AEHI who took part in the Netherlands Cohort Study on Acute HIV infection (NOVA) in the Netherlands during 2015-2021. METHODS: Transmission clusters were identified using phylogenetic analyses based on HIV pol sequences. The Tamura-Nei model was used to estimate genetic distance. A number of 1000 bootstraps was used to check the reliability of clustering using maximum likelihood. A cluster was defined as having a bootstrap value of at least 95% and a genetic distance of at most 1.5%. Sensitivity analyses using different values for the bootstrap and genetic distance were performed to study the reproducibility of the clustering. RESULTS: Of the 156 participants included in NOVA between July 2015 and April 2021, 134 individuals for whom baseline characteristics and genotypic resistance data at baseline were available could be included. We identified 10 clusters, but the majority of persons (111/134) were not part of a cluster, suggesting mainly independent transmission events. CONCLUSION: Mainly independent transmission events among a study population consisting predominantly of MSM in a low-incidence high-resource setting is likely the result of active AEHI case finding and direct start of treatment, and the roll-out over recent years of preventive measures such as preexposure prophylaxis.

Outbreak of imported diphtheria with Corynebacterium diphtheriae among migrants arriving in Germany, 2022.

From July 2022, cases of imported diphtheria with toxigenic Corynebacterium diphtheriae remarkably increased among migrants arriving in Germany. Up to 30 September 2022, 44 cases have been reported to the national public health institute, all laboratory-confirmed, male, and mainly coming from Syria (n = 21) and Afghanistan (n = 17). Phylogeny and available journey information indicate that most cases (n = 19) were infected along the Balkan route. Active case finding, increased laboratory preparedness and epicentre localisation in countries along this route are important.

Online networks facilitating multidisciplinary healthcare: a novel strategy to curb COVID-19.

Objectives: Global spread of COVID-19 at an unprecedented speed has heavily strained healthcare systems worldwide, and reliable alternatives to analogue healthcare are urgently needed. Methods: During the first COVID-19 wave in the Netherlands, we launched six regional online networks and analysed the activity and content in a qualitative mixed-methods manner. Results: We observed continued activity and collaboration on the platform between healthcare professionals at the different levels of care. Conclusion: The networks described here were launched successfully and have the potential to optimise the COVID-19 response.

Cohort profile: the Netherlands Cohort Study on Acute HIV infection (NOVA), a prospective cohort study of people with acute or early HIV infection who immediately initiate HIV treatment.

PURPOSE: Initiation of combination antiretroviral therapy (cART) during acute or early HIV-infection (AEHI) limits the size of the viral reservoir and preserves immune function. This renders individuals who started cART during AEHI promising participants in HIV-cure trials. Therefore, we established a multicentre prospective cohort study in the Netherlands that enrols people with AEHI. In anticipation of future cure trials, we will longitudinally investigate the properties of the viral reservoir size and HIV-specific immune responses among cohort participants. PARTICIPANTS: Participants immediately initiate intensified cART: dolutegravir, emtricitabine/tenofovir and darunavir/ritonavir (DRV/r). After 4 weeks, once baseline resistance data are available, DRV/r is discontinued. Three study groups are assembled based on the preparedness of individuals to participate in the extensiveness of sampling. Participants accepting immediate treatment and follow-up but declining additional sampling are included in study group 1 ('standard') and routine diagnostic procedures are performed. Participants willing to undergo blood, leukapheresis and semen sampling are included in study group 2 ('less invasive'). In study group 3 ('extended'), additional tissue (gut-associated lymphoid tissue, peripheral lymph node) and cerebrospinal fluid sampling are performed. FINDINGS TO DATE: Between 2015 and 2020, 140 individuals with AEHI have been enrolled at nine study sites. At enrolment, median age was 36 (IQR 28-47) years, and 134 (95.7%) participants were men. Distribution of Fiebig stages was as follows: Fiebig I, 3 (2.1%); II, 20 (14.3%); III, 7 (5.0%); IV, 49 (35.0%); V, 39 (27.9%); VI, 22 (15.7%). Median plasma HIV RNA was 5.9 (IQR 4.7-6.7) log10 copies/mL and CD4 count 510 (IQR 370-700) cells/mm3. Median time from cART initiation to viral suppression was 8.0 (IQR 4.0-16.0) weeks. FUTURE PLANS: The Netherlands Cohort Study on Acute HIV infection remains open for participant enrolment and for additional sites to join the network. This cohort provides a unique nationwide platform for conducting future in-depth virological, immunological, host genetic and interventional studies investigating HIV-cure strategies.

Selective cell death in HIV-1-infected cells by DDX3 inhibitors leads to depletion of the inducible reservoir.

An innovative approach to eliminate HIV-1-infected cells emerging out of latency, the major hurdle to HIV-1 cure, is to pharmacologically reactivate viral expression and concomitantly trigger intracellular pro-apoptotic pathways in order to selectively induce cell death (ICD) of infected cells, without reliance on the extracellular immune system. In this work, we demonstrate the effect of DDX3 inhibitors on selectively inducing cell death in latent HIV-1-infected cell lines, primary CD4+ T cells and in CD4+ T cells from cART-suppressed people living with HIV-1 (PLWHIV). We used single-cell FISH-Flow technology to characterise the contribution of viral RNA to inducing cell death. The pharmacological targeting of DDX3 induced HIV-1 RNA expression, resulting in phosphorylation of IRF3 and upregulation of IFNß. DDX3 inhibition also resulted in the downregulation of BIRC5, critical to cell survival during HIV-1 infection, and selectively induced apoptosis in viral RNA-expressing CD4+ T cells but not bystander cells. DDX3 inhibitor treatment of CD4+ T cells from PLWHIV resulted in an approximately 50% reduction of the inducible latent HIV-1 reservoir by quantitation of HIV-1 RNA, by FISH-Flow, RT-qPCR and TILDA. This study provides proof of concept for pharmacological reversal of latency coupled to induction of apoptosis towards the elimination of the inducible reservoir.

Hypothetical questionnaires may overestimate willingness to participate in HIV cure research: Comparison of a cross-sectional survey to actual willingness to participate in an HIV cure study in the Netherlands.

OBJECTIVE: Little is known about willingness among people living with HIV (PLHIV) to participate in HIV cure research in the Netherlands. We compared results of a cross-sectional questionnaire assessing hypothetical willingness to actual willingness among PLHIV to take part in a clinical HIV cure trial. METHODS: Between March and June 2018, PLHIV visiting the outpatient clinic of a university hospital in the Netherlands were asked to complete a questionnaire about HIV cure research. Results were compared to the number of PLHIV willing to take part in an actual HIV cure study at the same center during an overlapping time period. RESULTS: In total, 165 participants, predominantly male (80%) from Western European countries (61%) completed the questionnaire. The majority would participate in cure research (n â€‹= â€‹111, 67%). Separately, actual willingness among PLHIV to participate in an HIV cure study was addressed in 312 cases. Apart from gender (96% male), baseline characteristics were comparable. Less than half expressed actual willingness to participate in the study (n â€‹= â€‹135, 43%). CONCLUSIONS: Hypothetical willingness to participate in cure-related research was high among PLHIV who completed the questionnaire. Actual willingness among eligible PLHIV to take part in an HIV cure study was much lower. Our findings show that questionnaires may overestimate willingness to participate in HIV cure trials and indicate that reasons for refusal in actual research should be further explored.

Inter-Laboratory Reproducibility of Inducible HIV-1 Reservoir Quantification by TILDA.

Substantial efforts to eliminate or reduce latent HIV-1 reservoirs are underway in clinical trials and have created a critical demand for sensitive, accurate, and reproducible tools to evaluate the efficacy of these strategies. Alternative reservoir quantification assays have been developed to circumvent limitations of the quantitative viral outgrowth assay. One such assay is tat/rev induced limiting dilution assay (TILDA), which measures the frequency of CD4+ T cells harboring inducible latent HIV-1 provirus. We modified pre-amplification reagents and conditions (TILDA v2.0) to improve assay execution and first internally validated assay performance using CD4+ T cells obtained from cART-suppressed HIV-1-infected individuals. Detection of tat/rev multiply spliced RNA was not altered by modifying pre-amplification conditions, confirming the robustness of the assay, and supporting the technique's amenability to limited modifications to ensure better implementation for routine use in clinical studies of latent HIV-1 reservoirs. Furthermore, we cross-validated results of TILDA v2.0 and the original assay performed in two separate laboratories using samples from 15 HIV-1-infected individuals. TILDA and TILDA v2.0 showed a strong correlation (Lin's Concordance Correlation Coefficient = 0.86). The low inter-laboratory variability between TILDAs performed at different institutes further supports use of TILDA for reservoir quantitation in multi-center interventional HIV-1 Cure trials.

Effect of Text Message, Phone Call, and In-Person Appointment Reminders on Uptake of Repeat HIV Testing among Outpatients Screened for Acute HIV Infection in Kenya: A Randomized Controlled Trial.

BACKGROUND: Following HIV-1 acquisition, many individuals develop an acute retroviral syndrome and a majority seek care. Available antibody testing cannot detect an acute HIV infection, but repeat testing after 2-4 weeks may detect seroconversion. We assessed the effect of appointment reminders on attendance for repeat HIV testing. METHODS: We enrolled, in a randomized controlled trial, 18-29 year old patients evaluated for acute HIV infection at five sites in Coastal Kenya (ClinicalTrials.gov NCT01876199). Participants were allocated 1:1 to either standard appointment (a dated appointment card) or enhanced appointment (a dated appointment card plus SMS and phone call reminders, or in-person reminders for participants without a phone). The primary outcome was visit attendance, i.e., the proportion of participants attending the repeat test visit. Factors associated with attendance were examined by bivariable and multivariable logistic regression. PRINCIPAL FINDINGS: Between April and July 2013, 410 participants were randomized. Attendance was 41% (85/207) for the standard group and 59% (117/199) for the enhanced group, for a relative risk of 1.4 [95% Confidence Interval, CI, 1.2-1.7].Higher attendance was independently associated with older age, study site, and report of transactional sex in past month. Lower attendance was associated with reporting multiple partners in the past two months. CONCLUSIONS: Appointment reminders through SMS, phone calls and in-person reminders increased the uptake of repeat HIV test by forty percent. This low-cost intervention could facilitate detection of acute HIV infections and uptake of recommended repeat testing. TRIAL REGISTRATION: Clinicaltrials.gov NCT01876199.

Engaging young adult clients of community pharmacies for HIV screening in Coastal Kenya: a cross-sectional study.

BACKGROUND: Adults in developing countries frequently use community pharmacies as the first and often only source of care. The objective of this study was to assess the success of pharmacy referrals and uptake of HIV testing by young adult clients of community pharmacies in the context of a screening programme for acute HIV-1 infection (AHI). METHODS: We requested five pharmacies to refer clients meeting predefined criteria (ie, 18-29 years of age and requesting treatment for fever, diarrhoea, sexually transmitted infection (STI) symptoms or body pains) for HIV-1 testing and AHI screening at selected clinics. Using multivariable logistical regression, we determined client characteristics associated with HIV-1 test uptake. RESULTS: From February through July 2013, 1490 pharmacy clients met targeting criteria (range of weekly averages across pharmacies: 4-35). Of these, 1074 (72%) accepted a referral coupon, 377 (25%) reported at a study clinic, 353 (24%) were HIV-1 tested and 127 (9%) met criteria for the AHI study. Of those tested, 14 (4.0%) were HIV-1 infected. Test uptake varied significantly by referring pharmacy and was higher for clients who presented at the pharmacy without a prescription versus those with a prescription, and for clients who sought care for STI symptoms. CONCLUSIONS: About a quarter of targeted pharmacy clients took up HIV-1 testing. Clients seeking care directly at the pharmacy (ie, without a prescription) and those with STI symptoms were more likely to take up HIV-1 testing. Engagement of adult pharmacy clients for HIV-1 screening may identify undiagnosed individuals and offers opportunities for HIV-1 prevention research.

Diagnosing acute and prevalent HIV-1 infection in young African adults seeking care for fever: a systematic review and audit of current practice.

Fever is a common complaint in HIV-1 infected adults and may be a presenting sign of acute HIV-1 infection (AHI). We investigated the extent to which HIV-1 infection was considered in the diagnostic evaluation of febrile adults in sub-Saharan Africa (SSA) through a systematic review of published literature and guidelines in the period 2003-2014. We also performed a detailed audit of current practice for the evaluation of febrile young adults in coastal Kenya. Our review identified 43 studies investigating the aetiology of fever in adult outpatients in SSA. While the guidelines identified recommend testing for HIV-1 infection, none mentioned AHI. In our audit of current practice at nine health facilities, only 189 out of 1173 (16.1%) patients, aged 18-29 years, were tested for HIV-1. In a detailed record review, only 2 out of 39 (5.1%) young adults seeking care for fever were tested for HIV-1, and the possibility of AHI was not mentioned. Available literature on adult outpatients presenting with fever is heavily focused on diagnosing malaria and guidelines are poorly defined in terms of evaluating aetiologies other than malaria. Current practice in coastal Kenya shows poor uptake of provider-initiated HIV-1 testing and AHI is not currently considered in the differential diagnosis.

Acute HIV-1 infection is as common as malaria in young febrile adults seeking care in coastal Kenya.

BACKGROUND: Febrile adults are usually not tested for acute HIV-1 infection (AHI) in Africa. We assessed a strategy to diagnose AHI among young adult patients seeking care. METHODS: Young adults (<30 years) who met predefined AHI criteria at care seeking, including fever, sexually transmitted disease symptoms, diarrhoea, body pains or multiple partners were referred from five pharmacies and screened at five health facilities. Prevalent HIV-1 was diagnosed by nationally recommended serial rapid HIV-1 testing. Willing HIV-1-negative patients were evaluated for AHI, defined as a positive p24 antigen test, and subsequent seroconversion or RNA detection. Febrile patients evaluated for AHI were also screened for malaria using a rapid test, with PCR confirmation of positives. RESULTS: In 3602 adults seeking care, overall HIV-1 prevalence was 3.9%: 7.6% (68/897) among patients meeting AHI criteria vs. 2.6% (71/2705) among those who did not (P < 0.001). AHI was diagnosed in five of 506 HIV-1-negative or discordant patients who met AHI risk criteria and were completely evaluated [prevalence 1.0%, 95% confidence interval (CI) 0.3-2.3%]. Of these five AHI cases, four were diagnosed among the 241 patients with fever (prevalence 1.7%, 95% CI 0.5-4.2%), vs. one among 265 non-febrile patients (prevalence 0.4%, 95% CI 0.0-2.0%, P = 0.1). Malaria was confirmed by PCR in four (1.7%) of the 241 febrile patients. CONCLUSION: AHI was as common as confirmed malaria in young febrile adults seeking care. An AHI detection strategy targeting young febrile adults seeking care at pharmacies and health facilities is feasible and should be considered as an HIV-prevention strategy in high-transmission settings.

The challenge of evaluating health effects of organic food; operationalisation of a dynamic concept of health.

The health benefits of consuming organically produced foods compared with conventional foods are unclear. Important obstacles to drawing clear conclusions in this field of research are (1) the lack of a clear operational definition of health and (2) the inability to distinguish between different levels of health using valid biomarkers. In this paper, some shortcomings of the current definition of health are outlined and the relevance of integrating a more dynamic and functional component is emphasised, which is reflected by the ability to adapt. The state of health could then be determined by challenging an individual with some form of stressor and by subsequent quantification and evaluation of the coherence in recovery of various physiological processes and parameters. A set of relevant parameters includes the activity of the immune system and the activity of the autonomous nervous system. A good recovery towards homeostasis is suggested to reflect a qualitatively good state of health. Furthermore, it would enable objective evaluation of health-optimising strategies, including the consumption of organically produced foods that aim to strengthen health.